Identification of Plasma Metabolomic Biomarkers of Juvenile Idiopathic Arthritis.

Identification of disease and therapeutic biomarkers remains a significant challenge in the early diagnosis and effective treatment of juvenile idiopathic arthritis (JIA). In this study, plasma metabolomic profiling was conducted to identify disease-related metabolic biomarkers associated with JIA. Plasma samples from treatment-naïve JIA patients and non-JIA reference patients underwent global metabolomic profiling across discovery (60 JIA, 60 non-JIA) and replication (49 JIA, 38 non-JIA) cohorts.

Evaluating the impact of a flipped classroom model based on cognitive science of learning strategies in a pharmacotherapy course.

Introduction: The purpose of this study was to determine the impact of a flipped classroom method based on cognitive science of learning strategies on student performance and experience in a third-year pharmacotherapy course.

Methods: The cognitive science of learning flipped classroom (CSL-FC) strategies in this study included pre-class learning (Preview), in-class application to cases (Retrieval), after-class learning (Spaced Retrieval), and post-module reflection (Deliberate Reflection) in a required pharmacotherapy course. During fall 2017, one instructor piloted the CSL-FC method.

Plasma metabolomic profiling as a tool to identify predictive biomarkers of methotrexate efficacy in rheumatoid arthritis.

Objective: Methotrexate (MTX) remains the first-choice disease-modifying therapy in rheumatoid arthritis (RA). However, clinical response is variable, and no reliable predictive biomarkers of efficacy currently exist. In this study, plasma metabolomic profiling is evaluated as a tool to identify pretreatment biomarkers of MTX response in RA.

Methotrexate Disposition, Anti-Folate Activity, and Metabolomic Profiling to Identify Molecular Markers of Disease Activity and Drug Response in the Collagen-Induced Arthritis Mouse Model.

Methotrexate (MTX) is widely used in the treatment of autoimmune arthritis but is limited by its unpredictable and variable response profile. Currently, no biomarkers exist to predict or monitor early therapeutic responses to MTX. Using a collagen-induced arthritis (CIA) mouse model, this study aimed to identify biochemical pathways and biomarkers associated with MTX efficacy in autoimmune arthritis.

Metabolomic Profiling Identifies Exogenous and Microbiota-Derived Metabolites as Markers of Methotrexate Efficacy in Juvenile Idiopathic Arthritis.

Variability in methotrexate (MTX) efficacy represents a barrier to early and effective disease control in the treatment of juvenile idiopathic arthritis (JIA). This work seeks to understand the impact of MTX on the plasma metabolome and to identify metabolic biomarkers of MTX efficacy in a prospective cohort of children with JIA. Plasma samples from a cohort of children with JIA ( = 30) collected prior to the initiation of MTX and after 3 months of therapy were analyzed using a semi-targeted global metabolomic platform detecting 673 metabolites across a diversity of biochemical classes.

Plasma Metabolome Normalization in Rheumatoid Arthritis Following Initiation of Methotrexate and the Identification of Metabolic Biomarkers of Efficacy.

Methotrexate (MTX) efficacy in the treatment of rheumatoid arthritis (RA) is variable and unpredictable, resulting in a need to identify biomarkers to guide drug therapy. This study evaluates changes in the plasma metabolome associated with response to MTX in RA with the goal of understanding the metabolic basis for MTX efficacy towards the identification of potential metabolic biomarkers of MTX response. Plasma samples were collected from healthy control subjects ( = 20), and RA patients initiating MTX therapy ( = 20, 15 mg/week) before and after 16 weeks of treatment.

Low Etanercept Concentrations in Children With Obesity and Juvenile Idiopathic Arthritis.

Objective: To evaluate the impact of obesity on etanercept (ETN) drug exposure in children with juvenile idiopathic arthritis (JIA).

Methods: We conducted a pilot, cross-sectional, observational study in a real-world cohort of children with JIA receiving ETN as standard of care from a single center. We analyzed the relationship between body size and ETN plasma concentrations, adjusting for dosage.

Dose-dependent Pharmacological Response to Rituximab in the Treatment of Antineutrophil Cytoplasmic Antibody-associated Vasculitis.

Objective: Rituximab (RTX) is effective in the induction and maintenance of remission in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, uncertainty remains regarding the optimal maintenance dosing regimen. This work evaluates the relationship between variability in RTX dosing and pharmacological response in AAV.

A population physiologically-based pharmacokinetic model to characterize antibody disposition in pediatrics and evaluation of the model using infliximab.

Aims: In order to better predict the pharmacokinetics (PK) of antibodies in children, and to facilitate dose optimization of antibodies in paediatric patients, there is a need to develop systems PK models that integrate ontogeny-related changes in human physiological parameters.

Methods: A population-based physiological-based PK (PBPK) model to characterize antibody PK in paediatrics has been developed, by incorporating age-related changes in body weight, organ weight, organ blood flow rate and interstitial volumes in a previously published platform model. The model was further used to perform Monte Carlo simulations to investigate clearance vs.

Factors associated with reduced infliximab exposure in the treatment of pediatric autoimmune disorders: a cross-sectional prospective convenience sampling study.

Background: Inadequate systemic exposure to infliximab (IFX) is associated with treatment failure. This work evaluated factors associated with reduced IFX exposure in children with autoimmune disorders requiring IFX therapy.

Methods: In this single-center cross-sectional prospective study IFX trough concentrations and anti-drug antibodies (ADAs) were measured in serum from children diagnosed with inflammatory bowel disease (IBD) (n = 73), juvenile idiopathic arthritis (JIA) (n = 16), or uveitis (n = 8) receiving maintenance IFX infusions at an outpatient infusion clinic in a tertiary academic pediatric hospital.

Leveraging innovative technology to generate drug response phenotypes for the advancement of biomarker-driven precision dosing.

Although traditional approaches to biomarker discovery have elucidated key molecular markers that have improved drug selection (precision medicine), the discovery of biomarkers that inform optimal dose selection (precision dosing) continues to be a challenge in many therapeutic areas. Larger and more diverse study populations are necessary to discover additional biomarkers that provide the resolution needed for a more tailored dose. To generate and accommodate large datasets of drug response phenotypes, time- and cost-efficient strategies are necessary.

Defining a Therapeutic Window for Rituximab Maintenance Therapy in ANCA-Associated Vasculitis: A Longitudinal Observational Study.

Background/objective:: Rituximab (RTX) has been shown to be effective at maintaining remission in patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), however, the optimal regimen has not been established. The objective of this study was to determine the association between RTX exposure and pharmacological response.

Methods:: Thirty patients with GPA (25) and MPA (5) receiving maintenance therapy with RTX were longitudinally followed in a single tertiary care center.

Altered Folate Homeostasis in Children with Down Syndrome: A Potential Basis for Enhanced Methotrexate Toxicity.

Methotrexate is used to treat autoimmune and oncologic diseases in children with Down syndrome. However, increased methotrexate-related toxicity is reported in this population. We evaluated differences in the concentrations and distribution of erythrocyte folates in children with Down syndrome as a potential basis for this enhanced toxicity.

Metabolomic Profiling to Identify Molecular Biomarkers of Cellular Response to Methotrexate In Vitro.

Variation in methotrexate (MTX) efficacy represents a significant barrier to early and effective disease control in the treatment of autoimmune arthritis. We hypothesize that the utilization of metabolomic techniques will allow for an improved understanding of the biochemical basis for the pharmacological activity of MTX, and can promote the identification and evaluation of novel molecular biomarkers of MTX response. In this work, erythroblastoid cells were exposed to MTX at the physiologic concentration of 1,000 nM and analyzed using three metabolomic platforms to give a broad spectrum of cellular metabolites.

Precision Pharmacotherapy: Integrating Pharmacogenomics into Clinical Pharmacy Practice.

Precision pharmacotherapy encompasses the use of therapeutic drug monitoring; evaluation of liver and renal function, genomics, and environmental and lifestyle exposures; and analysis of other unique patient or disease characteristics to guide drug selection and dosing. This paper articulates real-world clinical applications of precision pharmacotherapy, focusing exclusively on the emerging field of clinical pharmacogenomics. This field is evolving rapidly, and clinical pharmacists now play an invaluable role in the clinical implementation, education, and research applications of pharmacogenomics.

Methotrexate disposition, anti-folate activity and efficacy in the collagen-induced arthritis mouse model.

Methotrexate (MTX) efficacy in autoimmune arthritis is variable and unpredictable resulting in the need for the identification of biomarkers to guide drug therapy. This study utilizes the collagen-induced arthritis mouse model to investigate erythrocyte MTX disposition and anti-folate activity as biochemical markers of efficacy in autoimmune arthritis. Following induction of arthritis, DBA/1J mice were treated with once-weekly subcutaneous MTX at varying doses over a period of 40 days.

Nicotinamide Phosphoribosyltransferase Deficiency Potentiates the Antiproliferative Activity of Methotrexate through Enhanced Depletion of Intracellular ATP.

Lower plasma nicotinamide phosphoribosyltransferase (NAMPT) levels are associated with improved response to methotrexate (MTX) in patients with juvenile idiopathic arthritis. Cell-based studies confirmed that reduced cellular NAMPT activity potentiates the pharmacologic activity of MTX; however, the mechanism of this interaction has yet to be defined. Therefore, in this study, we investigate the mechanism of enhanced pharmacologic activity of MTX in NAMPT-deficient A549 cells.

Variability in Potency Among Commercial Preparations of Berberine.

Berberine is an isoquinoline alkaloid plant extract that is widely available as a dietary supplement in the United States and has demonstrated efficacy in the treatment of type 2 diabetes mellitus and dyslipidemia. Because of its increased use and purported pharmacological properties, potential variations in product quality could pose a barrier to berberine's safety and effectiveness in clinical practice. Thus, this study evaluated the potency of dietary supplements containing berberine available in the U.

Cytokine Biomarkers of Disease Activity and Therapeutic Response after Initiating Methotrexate Therapy in Patients with Juvenile Idiopathic Arthritis.

Study Objective: To evaluate the relationship between plasma cytokine levels with disease activity and therapeutic response in patients with juvenile idiopathic arthritis (JIA) after initiating methotrexate (MTX) therapy.

Design: Single-center observational prospective cohort study.

Setting: Outpatient pediatric rheumatology clinic at a tertiary care academic pediatric hospital.

Development of Extemporaneously Compounded Aripiprazole Oral Suspensions for Use in Children.

The purpose of this study was to develop extemporaneously compounded oral liquid formulations of aripiprazole for use in pediatric patients and those patients unable to swallow the solid oral dosage forms. Aripiprazole tablets(30 mg) were ground to a fine powder and suspended at a concentration of 1.0 mg/mL in either a 1:1 blend of Ora-Plus and Ora-Sweet, or 1% methylcellulose and Simple Syrup NF.

Folate depletion and increased glutamation in juvenile idiopathic arthritis patients treated with methotrexate.

Objective: Folates exist as a fluctuating pool of polyglutamated metabolites that may serve as a clinical marker of methotrexate (MTX) activity. This study was undertaken to evaluate circulating folate content and folate polyglutamate distribution in juvenile idiopathic arthritis (JIA) patients and in a cell culture model based on MTX exposure and folate supply.

Methods: Blood, plasma, and red blood cell (RBC) measurements of MTX and folates were obtained from previously published data sets and an additional analysis of JIA patients receiving MTX (n = 98) and those not receiving MTX (n = 78).

Low-dose methotrexate results in the selective accumulation of aminoimidazole carboxamide ribotide in an erythroblastoid cell line.

Therapeutic and toxic response to low-dose methotrexate (MTX) in the treatment of autoimmune disease continues to be highly variable, resulting in a critical need to identify predictive biomarkers of response. Biomarker development has been hampered by an incomplete understanding of the molecular pharmacology of low-dose MTX. To address this issue, accumulation of the substrates for aminoimidazole carboxamide ribonucleotide transformylase (AICART) and thymidylate synthase (TS) was measured as markers of pharmacological activity of MTX in an erythroblastoid cell line.